Tnf-alpha inhibitors

ABSTRACT

TNF-α inhibitors containing a heterocyclic compound having angiotensin II antagonistic activity which are useful as preventives/remedies for inflammatory diseases, etc.

FIELD OF THE INVENTION

[0001] The present invention relates to a TNF-α inhibitor which containsa heterocyclic compound having an angiotensin II antagonistic activity,its prodrug or a salt thereof and which is useful as preventives orremedies for an inflammatory disease and the like.

BACKGROUND ART

[0002] A TNF (tumor necrosis factor)-α is believed to play an importantrole in various diseases. For example, chronic rheumatoid arthritis thatis an inflammatory disease involves an increased TNF-α production whichmay lead to the destruction of an articular tissue.

[0003] A TNF-α inhibitor which has sufficiently excellent pharmaceuticalcharacteristics such as an excellent prophylactic or therapeutic effectfor an inflammatory disease and no side effects, is desired to bedeveloped.

DISCLOSURE OF THE INVENTION

[0004] In view of these circumstances described above, the presentinventors made an effort to develop an agent useful in inhibiting aTNF-α, and found eventually that a heterocyclic compound having anangiotensin II antagonistic activity, especially a compound having anangiotensin II(AII) antagonistic activity which is represented by acertain structural formula, is extremely effective in inhibiting aTNF-α, and a further investigations were made on the basis of thisknowledge and the present invention was completed.

[0005] That is, the present invention relates to:

[0006] (1) A TNF-α inhibitor comprising a heterocyclic compound havingan angiotensin II antagonistic activity (a heterocyclic compound havingan angiotensin II receptor-antagonistic action) which is represented bythe formula:

[0007]  wherein ring B is an optionally substituted nitrogen-containingheterocyclic ring, R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, and n is an integer of 1 or 2 (except for thecompound represented by the formula:

[0008] [5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one]),its prodrug or a salt thereof;

[0009] (2) An agent according to the above-mentioned (1), wherein theheterocyclic compound is a compound having an oxygen atom in itsmolecule;

[0010] (3) An agent according to the above-mentioned (1), wherein theheterocyclic compound is a compound having an ether bond or a carbonylgroup;

[0011] (4) An agent according to the above-mentioned (1), wherein ring Bis an optionally substituted nitrogen-containing aromatic heterocyclicring;

[0012] (5) An agent according to the above-mentioned (1), wherein ring Bis an optionally substituted 5- to 6-membered nitrogen-containingheterocyclic ring;

[0013] (6) An agent according to the above-mentioned (1), wherein ring Bis an optionally substituted imidazole ring;

[0014] (7) An agent according to the above-mentioned (1),wherein theheterocyclic compound is a compound represented by the formula (I):

[0015]  wherein R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, n is an integer of 1 or 2, ring A is a furtheroptionally substituted benzene ring, R² is a group capable of forming ananion or a group capable of being converted into such a group, R³ is anoptionally substituted hydrocarbon residue which may be bound through aheteroatom;

[0016] (8) An agent according to the above-mentioned (1), wherein theheterocyclic compound is losartan, eprosaltan, candesartan cilexetil,candesartan, telmisartan, irbesartan, olmesartan or tasosartan;

[0017] (9) An agent according to the above-mentioned (1), wherein theheterocyclic compound is2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid;

[0018] (10) An agent according to the above-mentioned (1), wherein theheterocyclic compound is1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate;

[0019] (11) An agent according to the above-mentioned (1), wherein theheterocyclic compound is2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid;

[0020] (12) An agent according to the above-mentioned (1), which is aprophylactic and therapeutic agent for a disease involving a TNF-α(e.g., a disease which is developed or exacerbated as a result of thepresence of a TNF-α);

[0021] (13) An agent according to the above-mentioned (1), which is ananti-inflammatory agent;

[0022] (14) Use of a heterocyclic compound having an angiotensin IIantagonistic activity, its prodrug or a salt thereof for inhibiting aTNF-α;

[0023] (15) Use of a heterocyclic compound having an angiotensin IIantagonistic activity, its prodrug or a salt thereof for the manufactureof a medicament for inhibiting a TNF-α;

[0024] (16) A method for inhibiting a TNF-α in mammals comprisingadministering to a mammal an effective dose of a heterocyclic compoundhaving an angiotensin II antagonistic activity which is represented bythe formula:

[0025]  wherein ring B is an optionally substituted nitrogen-containingheterocyclic group, R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, and n is an integer of 1 or 2 (except for5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one),its prodrug or a salt thereof;

[0026] (17) Use of a heterocyclic compound having an angiotensin IIantagonistic activity which is represented by the formula:

[0027]  wherein ring B is an optionally substituted nitrogen-containingheterocyclic group, R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, and n is an integer of 1 or 2 (except for5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one),its prodrug or a salt thereof for the manufacture of a TNF-α inhibitor;and the like.

[0028] A heterocyclic compound having an angiotensin II antagonisticactivity according to the present invention, its prodrug or a saltthereof, can be employed advantageously for inhibiting a TNF-α (e.g.,inhibiting a TNF-α by inhibiting the production of a TNF-α or byinhibiting a TNF-α receptor).

[0029] An angiotensin II-antagonistic activity according to the presentinvention means a competitive or non-competitive inhibitory effect onthe binding of angiotensin II to an angiotensin II receptor on a cellmembrane which lead to a reduction in a potent vasoconstrictive effector vascular smooth muscle-proliferating effect induced by angiotensin.

[0030] A heterocyclic compound having an angiotensin II antagonisticactivity used in this invention is preferably a non-peptide heterocycliccompound having an antagonistic activity exhibiting an advantageouslyprolonged duration of action. Such a heterocyclic compound having anangiotensin II antagonistic activity is preferably a compound having anoxygen atom in its molecule, above all, preferably a compound having anether bond or a carbonyl group (said carbonyl group may be conjugated toform a hydroxyl group), more preferably a compound having ether bond ora ketone derivative, and most preferably an ether derivative.

[0031] In the formula above, an “optionally substitutednitrogen-containing heterocyclic ring” represented by ring B ispreferably an optionally substituted nitrogen-containing aromaticheterocyclic ring. Such an “optionally substituted nitrogen-containingheterocyclic ring” represented by ring B is preferably an optionallysubstituted 5- to 6-membered nitrogen-containing heterocyclic ring,especially an optionally substituted 5- to 6-memberednitrogen-containing aromatic heterocyclic ring (e.g., a ring which maybe fused to an optionally substituted aromatic ring such as a benzenering (which may have a substituent group similar to that exemplified asa substituent group on ring A described below), an optionallysubstituted imidazole ring; typically, an optionally substitutedimidazole ring, an optionally substituted benzimidazole ring). Asubstituent group which may be possessed by a “nitrogen-containingheterocyclic ring” in an “optionally substituted nitrogen-containingheterocyclic ring” represented by ring B may for example be asubstituent group similar to that exemplified as a substituent group onring A described below.

[0032] While a non-peptide heterocyclic compound having an angiotensinII antagonistic activity is not limited particularly, those which may beexemplified are imidazole derivatives disclosed in JP-A-56-71073,JP-A-56-71074, JP-A-57-98270, JP-A-58-157768, U.S. Pat. No. 4,355,040and U.S. Pat. No. 4,340,598 and the like, modified imidazole derivativesdisclosed in EP-253310, EP-291969, EP-324377, EP-403158, WO-9100277,JP-A-63-23868 and JP-A-1-117876 and the like, pyrrole, pyrazole andtriazole derivatives disclosed in U.S. Pat. No. 5,183,899, EP-323841,EP-409332 and JP-A-1-287071 and the like, benzimidazole derivativesdisclosed in U.S. Pat. No. 4,880,804, EP-0392317, EP-0399732,EP-0400835, EP-425921, EP-459136 and JP-A-3-63264 and the like,azaindene derivatives disclosed in EP-399731 and the like, pyrimidonederivatives disclosed in EP-407342 and the like, quinazoline derivativesdisclosed in EP-411766 and the like, xanthine derivatives disclosed inEP-430300 and the like, condensed imidazole derivatives disclosed inEP-434038 and the like, pyrimidinedione derivatives disclosed inEP-442473 and the like, thienopyridone derivatives disclosed inEP-443568 as well as heterocyclic compounds disclosed in EP-445811,EP-483683, EP-518033, EP-520423, EP-588299, EP-603712 and the like.Among those listed above, representative compounds are found also inJournal of Medicinal Chemistry, Vol.39, No.3, p.625-656, 1996. Anon-peptide heterocyclic compound having an angiotensin II antagonisticactivity may also be any other nonpeptidic heterocyclic compound havingan angiotensin II antagonistic activity than the compounds found in thereference describe above, and those employed preferably are losartan(DuP753), eprosartan (SK&F108566), candesartan cilexetil (TCV-116),telmisartan (BIBR277), irbesartan (SR47436), tasosartan (ANA-756),olmesartan and metabolically activated substances thereof (such ascandesartan).

[0033] As a heterocyclic compound having an angiotensin II antagonisticactivity, a benzimidazole derivative represented by the formula (I):

[0034] wherein R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, n is an integer of 1 or 2, ring A is a furtheroptionally substituted benzene ring, R² is a group capable of forming ananion or a group capable of being converted into such a group, R³ is anoptionally substituted hydrocarbon residue which may be bound through aheteroatom (preferably an optionally substituted hydrocarbon residuebound through an oxygen atom) or its salt is employed preferably.

[0035] In the formula above, the group represented by R¹ which iscapable of forming an anion (group having a hydrogen atom capable ofbeing released as a proton) may for example be (1) a carboxyl group, (2)a tetrazolyl group, (3) a trifluoromethanesulfonamide group (—NHSO₂CF₃),(4) a phosphoric acid group, (6) a sulfonic acid group, (6) a 5- to7-membered (preferably 5- to 6-membered), monocyclic, optionallysubstituted heterocyclic residue containing one or more than twoheteroatoms selected from N, S and O.

[0036] A “5- to 7-membered (preferably 5- to 6-membered), monocyclic,optionally substituted heterocyclic residue containing one or more thantwo heteroatoms selected from N, S and O” described above may forexample be:

[0037] and the bond between a heterocyclic residue represented by R¹ anda phenyl group to which said heterocyclic residue is bound may not onlybe a carbon-carbon bond shown above but also be a bond through one ofseveral nitrogen atoms when g in the formula shown above represents—NH—. For example, when R¹ is represented by the formula:

[0038] the following types of bond:

[0039] are specifically included. Other nitrogen atom-mediated bondsinclude those represented by the formulae:

[0040] In the formulae above, g is —CH₂—, —NH—, —O— or —S(O)_(m)—, andeach of >=Z, >=Z′ and >=Z″ is a carbonyl group, thiocarbonyl group or anoptionally oxidized sulfur atom respectively (e.g., S, S(O), S(O)₂ andthe like) (preferably carbonyl or thiocarbonyl group, more preferablycarbonyl group), and m is an integer of 0, 1 or 2.

[0041] Preferably a heterocyclic residue represented by R¹ may forexample be a group having an —NH— or —OH group as a proton donortogether with a carbonyl group, thiocarbonyl group or sulfinyl group asa proton acceptor such as an oxadiazolone ring, oxadiazolothione ring orthiadiazolone ring. Further the heterocyclic residue represented by R¹may be taken together with a cyclic substituent to form a condensedring, in that case the heterocyclic residue represented by R¹ ispreferably a 5- to 6-membered ring residue, more preferably a 5-memberedring residue.

[0042] A heterocyclic residue represented by R¹ is preferably a grouprepresented by the formula:

[0043] wherein i is —O— or —S—, j is >=O, >=S or >=S(O)_(m), and m isdefined as described above (those preferred being2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl, especially,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl).

[0044] A heterocyclic residue (R¹) described above is present as atautomeric form as shown below. For example, when Z=O and g=O in theformula:

[0045] then three tautomeric forms a′, b′ and c′ represented by theformulae:

[0046] are present, and a heterocyclic residue represented by theformula:

[0047] is understood to include all of a′, b′ and c′ shown above.

[0048] The group represented by R′ which is capable of forming an anionmay be protected at a substitutable position by an optionallysubstituted lower (C₁₋₄) alkyl group or acyl group (e.g., lower (C₂₋₅)alkanoyl, benzoyl) and the like.

[0049] An optionally substituted lower (C₁₋₄) alkyl group may include,for example, (1) a lower (C₁₋₄) alkyl group which may be substituted by1 to 3 phenyl groups which may have a halogen atom, nitro, lower (C₁₋₄)alkyl, lower (C₁₋₄) alkoxy and the like (e.g., methyl, triphenylmethyl,p-methoxybenzyl, p-nitrobenzyl), (2) a lower (C₁₋₄) alkoxy-lower (C₁₋₄)alkyl group (e.g., methoxymethyl, ethoxymethy), and (3) a grouprepresented by the formula: —CH(R⁴)—OCOR⁵ [wherein R⁴ is (a) hydrogen,(b) a straight or branched lower alkyl group having 1 to 6 carbon atoms(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, isopentyl, neopentyl), (c) a straight or branched loweralkenyl group having 2 to 6 carbon atoms or (d) a cycloalkyl grouphaving 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl),and R⁵ is (a) a straight or branched lower alkyl group having 1 to 6carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl), (b) astraight or branched lower alkenyl group having 2 to 6 carbon atoms, (c)a lower alkyl group having 1 to 3 carbon atoms which is substituted by acycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl,cyclohexyl, cycloheptyl) or an optionally substituted aryl group (e.g.,phenyl or naphthyl group which may have a halogen atom, nitro, lower(C₁₋₄) alkyl, lower (C₁₋₄) alkoxy) (e.g., benzyl, p-chlorobenzyl,phenethyl, cyclopentyl, methyl, cyclohexylmethyl), (d) a lower alkenylgroup having 2 to 3 carbon atoms which is substituted by a cycloalkylhaving 3 to 8 carbon atoms or an oprionally substituted aryl group(e.g., phenyl or naphthyl group which may have a halogen atom, nitro,lower (C₁₋₄) alkyl, lower (C₁₋₄) alkoxy) (e.g., group having alkenylmoiety such as vinyl, propenyl, allyl, isopropenyl, including cinnamyl),(e) an optionally substituted aryl group (e.g., phenyl or naphthyl groupwhich may have a halogen atom, nitro, lower (C₁₋₄) alkyl, lower (C₁₋₄)alkoxy, including phenyl, p-tolyl, naphthyl), (f) a straight or branchedlower alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy,n-pentyloxy, isopentyloxy, neopentyloxy), (g) a straight or branchedlower alkenyloxy group having 2 to 8 carbon atoms (e.g., allyloxy,isobutenyloxy),(h) a cycloalkyloxy group having 3 to 8 carbon atoms(e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), (i) a loweralkoxy group having 1 to 3 carbon atoms which is substituted by acycloalkyl having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl,cyclobutyl) or an optionally substituted aryl group (e.g., phenyl ornaphthyl group which may have a halogen atom, nitro, lower (C₁₋₄) alkyl,lower (C₁₋₄) alkoxy), (e.g., group having an alkoxy moiety such asmethoxy, ethoxy, n-propoxy and isopropoxy, including benzyloxy,phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy), (j) a loweralkenyloxy group having 2 to 3 carbon atoms which is substituted by acycloalkyl having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl,cycloheptyl) or an oprionally substituted aryl group (e.g., phenyl ornaphthyl group which may have a halogen atom, nitro, lower (C₁₋₄) alkyl,lower (C₁₋₄) alkoxy)) (e.g., group having an alkenyloxy moiety such asvinyloxy, propenyloxy, allyloxy and isopropenyloxy, includingcinnamyloxy) or (k) an optionally substituted aryloxy group (e.g.,phenoxy or naphthoxy group which may have a halogen atom, nitro, lower(C₁₋₄) alkyl and lower (C₁₋₄) alkoxy, including phenoxy, p-nitrophenoxy,naphthoxy).

[0050] The group represented by R¹ which is capable of forming an anionmay have, in addition to the protective groups described above such asan optionally substituted lower (C₁₋₄) alkyl group or acyl group (e.g.,lower (C₂₋₅) alkanoyl, benzoyl), a further substituent group such as anoptionally substituted lower (C₁₋₄) alkyl (for example, one similar toan “optionally substituted lower (C₁₋₄) alkyl group” exemplified aboveas a protective group for the group represented by R¹ which is capableof forming an anion), halogen atom, nitro, cyano, lower (C₁₋₄) alkoxy,and amino which may be substituted by one or two lower (C₁₋₄) alkyls.

[0051] In the formula above, the group represented by R¹ which iscapable of forming an anion (group having a hydrogen atom capable ofbeing released as a proton) may be a group capable of being convertedinto a group capable of forming an anion under a biolgical, i.e.,physiological condition (for example, as a result of an in vivo reactionsuch as oxidation, reduction or hydrolysis by an intravital enzyme)(i.e., prodrug), or may be a group capable of being converted into agroup capable of forming an anion represented by R¹ as a result of achemical reaction (i.e., synthetic intermediate), such as cyano,N-hydroxycarbamimidoyl group (—C(═N═OH)—NH₂) and the groups (1)˜(6)below which is protected by an optionally substituted lower (C₁₋₄) alkylgroup or acyl group; (1) a carboxyl group, (2) a tetrazolyl group, (3) atrifluoromethanesulfonamide group(—NHSO₂CF₃), (4) a phosphoric acidgroup, (5) a sulfonic acid group and (6) a 5- to 7-membered (preferably5- to 6-membered), monocyclic, optionally substituted heterocyclicresidue containing one or more than two heteroatoms selected from N, Sand O.

[0052] R¹ is preferably carboxyl, tetrazolyl or2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl), whichmay be protected by an optionally substituted lower (C₁₋₄) alkyl (e.g.,methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl,p-nitrobenzyl) or acyl group (e.g., lower (C₂₋₅) alkanoyl, benzoyl), orcyano, N-hydroxycarbamimidoyl (preferably cyano), and especiallypreferably tetrazolyl is used.

[0053] In the formula above, X denotes that adjacent phenylene group andphenyl group are bound directly or through a spacer having 2 or less ofatomic chains (preferably a direct bond), and such a spacer having 2 orless of atomic chains may be any divalent chain whose number of theatoms constituting the straight chain moiety is 1 or 2 and which mayhave a side chain. Those exemplified typically are a lower (C₁₋₄)alkylene whose number of the atoms constituting the straight chainmoiety is 1 or 2, —CO—, —O—, —S—, —NH—, —CO—NH—, —O—CH₂—, —S—CH₂—,—CH═CH— and the like.

[0054] In the formula above, n is an integer of 1 or 2 (preferably 1).

[0055] In the formula above, ring A is a benzene ring which may have afurther substituent group in addition to the substituent R², and such asubstituent group may include, for example, (1) a halogen (e.g., F, Cl,Br), (2) a cyano, (3) a nitro, (4) an optionally substituted lower(C₁₋₄) alkyl, (5) a lower (C₁₋₄) alkoxy, (6) an optionally substitutedamino group (e.g., amino, N-lower (C₁₋₄) alkylamino (e.g., methylamino),N,N-di lower (C₁₋₄) alkylamino (e.g., dimethylamino), N-arylamino (e.g.,phenylamino), alicyclic amino (e.g., morpholino, piperidino, piperazino,N-phenylpiperadino)), (7) a group represented by the formula: —CO-D′[wherein D′ is a hydroxyl group or a lower (C₁₋₄) alkoxy whose alkylmoiety may be substituted by a hydroxyl group, lower (C₁₋₄) alkoxy,lower (C₂₋₆) alkanoyloxy (e.g., acetoxy, pivaloyloxy), lower (C₁₋₆)alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy) or lower(C₃₋₆) cycloalkoxycarbonyloxy (e.g., cyclohexyloxycarbonyloxy), or (8)tetrazolyl, trifluoromethanesulfonamide group, phosphoric acid group orsulfonic acid group which may be protected by an optionally substitutedlower (C₁₋₄) alkyl (for example, one similar to an “optionallysubstituted lower (C₁₋₄) alkyl group” exemplified above as a protectivegroup for a group as R¹ which is capable of forming an anion) or acyl(e.g., lower (C₂₋₅) alkanoyl, benzoyl).

[0056] While 1 to 2 substituent groups listed above may occursimultaneously in the substitutable position on a benzene ring, afurther substituent group, other than the substituent R², which may bepossessed by the ring A is preferably an optionally substituted lower(C₁₋₄) alkyl (e.g., a lower (C₁₋₄) alkyl group which may be optionallysubstituted by a hydroxyl group, carboxyl group, halogen) and a halogen,and more preferably the ring A does not have any substituent group otherthan the substituent R².

[0057] In the formula above, the group represented by R² which iscapable of forming an anion (group having a hydrogen atom capable ofbeing released as a proton) may include, for example, (1) an optionallyesterified or amidated carboxyl group, (2) a tetrazolyl group, (3) atrifluoromethanesulfonamide group (—NHSO₂CF₃), (4) a phosphoric acidgroup, (5) a sulfonic acid group, and any of these groups may beprotected by an optionally substituted lower alkyl group (for example,one similar to an “optionally substituted lower (C₁₋₄) alkyl group”exemplified above as a protective group for the group represented by R′which is capable of forming an anion) or acyl group (e.g., lower (C₂₋₅)alkanoyl, benzoyl), and may be any group capable of forming an anion orcapable of being converted into such a group under a biolgical, i.e.,physiological condition (for example, as a result of an in vivo reactionsuch as oxidation, reduction or hydrolysis by an intravital enzyme) oras a result of a chemical reaction. An optionally esterified or amidatedcarboxyl represented by R² may include, for example, a group representedby the formula: —CO-D- [wherein D is (1) a hydroxyl group, (2) anoptionally substituted amino (e.g., amino, N-lower (C₁₋₄) alkylamino,N,N-di-lower (C₁₋₄) alkylamino) or (3) an optionally substituted alkoxy{e.g., (i) a lower (C₁₋₆) alkoxy group whose alkyl moiety may besubstituted by a hydroxyl group, an optionally substituted amino (e.g.,amino, N-lower (C₁₋₄) alkylamino, N,N-di-lower (C₁₋₄) alkylamino,piperidino, morpholino), halogen, lower (C₁₋₆) alkoxy, lower (C₁₋₆)alkylthio, lower (C₃₋₈) cycloalkoxy or an optionally substituteddioxolenyl (e.g., 5-methyl-2-oxo-1,3-dioxolen-4-yl), or (ii) a grouprepresented by the formula: —O—CH(R⁶)—OCOR⁷— [wherein R⁶ is (a)hydrogen, (b) a straight or branched lower alkyl group having 1 to 6carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl), (c) a straight orbranched lower alkenyl group having 2 to 6 carbon atoms or (d) acycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl,cyclohexyl, cycloheptyl), and R⁷ is (a) a straight or branched loweralkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neopentyl), (b) a straight or branched lower alkenyl group having 2 to 6carbon atoms, (c) a lower alkyl group having 1 to 3 carbon atoms whichis substituted by a cycloalkyl group having 3 to 8 carbon atoms (e.g.,cyclopentyl, cyclohexyl, cycloheptyl) or an optionally substituted arylgroup (e.g., phenyl or naphthyl group which may have a halogen atom,nitro, lower (C₁₋₄) alkyl, lower (C₁₋₄) alkoxy) (e.g., benzyl,p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl), (d) alower alkenyl group having 2 to 3 carbon atoms which is substituted by acycloalkyl having 3 to 8 carbon atoms or an optionally substituted arylgroup (e.g., phenyl or naphthyl group which may have a halogen atom,nitro, lower (C₁₋₄) alkyl, lower (C₁₋₄) alkoxy) (e.g., group havingalkenyl moiety such as vinyl, propenyl, allyl, isopropenyl, includingcinnamyl), (e) an optionally substituted aryl group (e.g., phenyl ornaphthyl group which may have a halogen atom, nitro, lower (C₁₋₄) alkyl,lower (C₁₋₄) alkoxy, including phenyl, p-tolyl, naphthyl), (f) astraight or branched lower alkoxy group having 1 to 6 carbon atoms(e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy), (g) astraight or branched lower alkenyloxy group having 2 to 8 carbon atoms(e.g., allyloxy, isobutenyloxy),(h) a cycloalkyloxy group having 3 to 8carbon atoms (e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), (i)a lower alkoxy group having 1 to 3 carbon atoms which is substituted bya cycloalkyl having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl,cycloheptyl) or an optionally substituted aryl group (e.g., phenyl ornaphthyl group which may have a halogen atom, nitro, lower (C₁₋₄) alkyl,lower (C₁₋₄) alkoxy), (e.g., group having an alkoxy moiety such asmethoxy, ethoxy, n-propoxy and isopropoxy, including benzyloxy,phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy), (j) a loweralkenyloxy group having 2 to 3 carbon atoms which is substituted by acycloalkyl having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl,cycloheptyl) or an oprionally substituted aryl group (e.g., phenyl ornaphthyl group which may have a halogen atom, nitro, lower (C₁₋₄) alkyl,lower (C₁₋₄) alkoxy)) (e.g., group having an alkenyloxy moiety such asvinyloxy, propenyloxy, allyloxy and isopropenyloxy, includingcinnamyloxy) or (k) an optionally substituted aryloxy group (e.g.,phenoxy or naphthoxy group which may have a halogen atom, nitro, lower(C₁₋₄) alkyl and lower (C₁₋₄)alkoxy, including phenoxy, p-nitrophenoxy,naphthoxy)]}].

[0058] As R², an optionally esterified carboxyl is preferred and thoseexemplified typically are —COOH and its salt, —COOMe, —COOEt, —COOtBu,—COOPr, pivaloyloxymethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl,propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl,isobutyryloxymethoxycarbonyl, 1-(ethoxycarbonyloxy)ethoxycarbonyl,1-(acetoxy)ethoxycarbonyl, 1-(isobutyryloxy)ethoxycarbonyl,cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl,cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl and the like,and may be any group capable of forming an anion (e.g., COO⁻ or itsderivatives) or capable of being converted into such a group under abiolgical, i.e., physiological condition (for example, as a result of anin vivo reaction such as oxidation, reduction or hydrolysis by an invivo enzyme) or as a result of a chemical reaction, and also may be acarboxyl group or its prodrugs.

[0059] As R² described above, a group represented by the formula:—CO-D[wherein D is (1) a hydroxyl group or (2) a lower (C₁₋₄) alkoxygroup whose alkyl moiety may be substituted by a hydroxyl group, amino,halogen, lower (C₂₋₆) alkanoyloxy (e.g., acetoxy, pivaloyloxy), lower(C₃₋₈) cycloalkanoyloxy, lower (C₁₋₆) alkoxycarbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy), lower (C₃₋₈)cycloalkoxycarbonyloxy (e.g., cyclohexyloxycarbonyloxy), lower (C₁₋₄)alkoxy or lower (C₃₋₈) cycloalkoxy] is preferred, among which a carboxylwhich is esterified with a lower (C₁₋₄) alkyl (preferably, methyl orethyl) is especially preferred.

[0060] In the formula above, a “hydrocarbon residue” in an “optionallysubstituted hydrocarbon residue which may be bound through a heteroatom”represented by R³ may include, for example, (1) an alkyl group, (2) analkenyl group, (3) an alkynyl group, (4) a cycloalkyl group, (5) an arylgroup, (6) an aralkyl group and the like, among which an alkyl group,alkenyl group and cycloalkyl group is preferred.

[0061] An alkyl group of (1) described above may be a straight orbranched lower alkyl group having about 1 to 8 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and the like.

[0062] An alkenyl group of (2) described above may be a straight orbranched lower alkenyl group having about 2 to 8 carbon atoms, forexample, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyland the like.

[0063] An alkynyl group of (3) described above may be a straight orbranched lower alkynyl group having about 2 to 8 carbon atoms, forexample, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octynyl and thelike.

[0064] A cycloalkyl group of (4) described above may be a lowercycloalkyl having about 3 to 6 carbon atoms, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0065] Any of the alkyl groups, alkenyl groups, alkynyl groups orcycloalkyl groups described above may be substituted by a hydroxylgroup, optionally substituted amino group (e.g., amino, N-lower (C₁₋₄)alkylamino, N,N-di-lower (C₁₋₄) alkylamino), halogen, lower (C₁₋₄)alkoxy group, lower (C₁₋₄) alkylthio group and the like.

[0066] An aralkyl group of (5) described above may for example be aphenyl-lower (C₁₋₄) alkyl such as benzyl and phenethyl, while an arylgroup of (6) described above may for example be phenyl.

[0067] An aralkyl group or aryl group described above may have, in anyposition of its benzene ring, for example, a halogen (e.g., F, Cl, Br),nitro, optionally substituted amino group (e.g., amino, N-lower (C₁₋₄)alkylamino, N,N-di-lower (C₁₋₄) alkylamino), lower (C₁₋₄) alkoxy (e.g.,methoxy, ethoxy), lower (C₁₋₄) alkylthio (e.g., methylthio, ethylthio),lower (C₁₋₄) alkyl (e.g., methyl, ethyl).

[0068] Among those listed above, a “hydrocarbon residue” in an“optionally substituted hydrocarbon residue which may be bound through aheteroatom” represented by R³ is preferably an optionally substitutedalkyl or alkenyl group (e.g., a lower (C₁₋₅) alkyl or lower (C₂₋₅)alkenyl group which may be substituted by a hydroxyl group, amino group,halogen or lower (C₁₋₄) alkoxy group), among which a lower (C₁₋₅) alkyl(more preferably ethyl) is especially preferred.

[0069] A “heteroatom” in an “optionally substituted hydrocarbon residuewhich may be bound through a heteroatom” represented by R³ may include,for example, —O—, —S(O)_(m) [m is an integer of 0 to 2], —NR′-[R′ is ahydrogen atom or a lower (C₁₋₄) alkyl], among which —O— is preferredespecially.

[0070] Among those listed above, R³ is preferably a lower (C₁₋₅) alkylor lower (C₂₋₅) alkenyl group which may be bound through —O—, —S(O)_(m)—[m is an integer of 0 to 2] or —NR′— [R′ is a hydrogen atom or lower(C₁₋₄) alkyl] and which may be substituted by a substituent groupselected from a hydroxy group, amino group, halogen and lower (C₁₋₄)alkoxy group, more preferably a lower (C₁₋₅) alkyl or lower (C₁₋₅)alkoxy (especially ethoxy).

[0071] Among heterocyclic compounds represented by the formula (I)having an angiotensin II antagonistic activity, abenzimidazole-7-carboxylic acid derivative represented by the formula(I)′:

[0072] wherein R′ is (1) a carboxyl group, (2) a tetrazolyl group, or(3) a group represented by the formula:

[0073] wherein i is —O— or —S—, j is >=0, >=S or >=S(O)_(m), and m isdefined as described above, ring A is a benzene ring which may besubstituted by an optionally substituted lower (C₁₋₄) alkyl (e.g., lower(C₁₋₄) alkyl which may be substituted by a hydroxyl group, carboxylgroup or halogen) or halogen in addition to the substituent R²(preferably a benzene ring which does not have any substituent groupother than the substituent R²), R² is a group represented by theformula:—CO-D [wherein D is (1) a hydroxyl group or (2) a lower (C₁₋₄)alkoxy group whose alkyl moiety may be substituted by a hydroxyl group,amino, halogen, lower (C₂₋₆) alkanoyloxy (e.g., acetoxy, pivaloyloxy),lower (C₃₋₈ ) cycloalkanoyloxy, lower (C₁₋₆) alkoxycarbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy), lower (C₃₋₈)cycloalkoxycarbonyloxy (e.g., cyclohexyloxycarbonyloxy), lower (C₁₋₄)alkoxy or lower (C₃₋₈) cycloalkoxy], R³ is a lower (C₁₋₅) alkyl or lower(C₂₋₅) alkenyl group which may be bound through —O—, —S(O)_(m)— [m is aninteger of 0 to 2] or —NR′— [R′ is a hydrogen atom or lower (C₁₋₄)alkyl] and which may be substituted by a substituent group selected froma hydroxy group, amino group, halogen and lower (C₁₋₄) alkoxy group(preferably a lower (C₁₋₅) alkyl or lower (C₁₋₅) alkoxy; more preferablyethoxy), or a pharmacologically acceptable salt thereof is preferable,among which2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid [candesartan], 1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate[candesartan cilexetil], pivaloyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate,2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or salts thereof are particularly preferable.

[0074] Any of the benzimidazole derivatives described above can beprepared by a known method such as those described for example inEP-425921, EP-459136, EP-553879, EP-578125, EP-520423, EP-668272 ormethods analogous thereto. When candesartan cilexetil is employed, it ispreferable to use a stable C-form crystal described in EP-459136.

[0075] A heterocyclic compound having an angiotensin II antagonisticactivity employed in the present invention or its prodrug may be itselfor in the form of its pharmacologically acceptable salt. Such salt, whensaid heterocyclic compound having an angiotensin II antagonisticactivity has an acidic group such as a carboxyl group, may include forexample a salt with an inorganic base (e.g., alkaline metals such assodium and potassium, alkaline earth metals such as calcium andmagnesium, transition metals such as zinc, iron and copper) or anorganic base (e.g., organic amines such as trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine and N,N′-dibenzylethylenediamine,basic amino acids such as arginine, lysine and ornithine).

[0076] When a heterocyclic compound having an angiotensin IIantagonistic activity has a basic group such as an amino group, saltwith an inorganic acid or an organic acid (e.g., hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonicacid, formic acid, acetic acid, propionic acid, trifluoroacetic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid) or with an acidic amino acid such as asparticacid and glutamic acid can be exemplified.

[0077] A prodrug of a heterocyclic compound having an angiotensin IIantagonistic activity employed in the present invention [hereinafterreferred to as AII-antagonizing compound] is a compound which isconverted into an AII-antagonizing compound as a result of a reactionwith an enzyme or gastric acid under an in vivo physiological condition,i.e., a compound which undergoes an enzymatic oxidation, reduction orhydrolysis to be converted into an AII-antagonizing compound, a compoundwhich undergoes a hydrolysis by gastric acid to be converted into anAII-antagonizing compound. A prodrug of an AII-antagonizing compound mayinclude, for example, a compound formed as a result of the acylation,alkylation or phosphorylation of an amino group of the AII-antagonizingcompound (e.g., a compound formed as a result of the eicosanoylation,alanylation, pentylaminocarbonylation,(5-mehtyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,tert-butylation of an amino group of the AII-antagonizing compound); acompound formed as a result of the acylation, alkylation,phosphorylation or boration of a hydroxyl group of the AII-antagonizingcompound (e.g., a compound formed as a result of the acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation, dimethylaminomethylcarbonylation of ahydroxyl group of the AII-antagonizing compound); and a compound formedas a result of the esterification or amidation of a carboxyl group ofthe AII-antagonizing compound (e.g., a compound formed as a result ofthe ethyl-esterification, phenyl-esterification,carboxymethyl-esterification, dimethylaminomethyl-esterification,pivaloyloxymethyl-esterification, ethoxycarbonyloxyethyl-esterification,phthalidyl-esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterification,cyclohexyloxycarbonyloxyethyl-esterification and methylamidation of acarboxyl group of the AII-antagonizing compound) and the like. Any ofthese compounds can be produced from an AII-antagonizing compound by amethod known per se.

[0078] A prodrug of an AII-antagonizing compound may be a compound whichis converted into an AII-antagonizing compound under a physiologicalcondition such as those described in “IYAKUHINNOKAIHATSU (Pharmaceuticaldevelopment), Vol.7, Molecular designing, p163 to 198, published in 1990by HIROKAWASHOTEN.

[0079] An AII-antagonizing compound may be a hydrate or anhydride.

[0080] A heterocyclic compound having an angiotensin II antagonisticactivity employed in the present invention or a pharmaceuticallyacceptable salt thereof has a low toxicity, and can be administered as aTNF-α inhibitor, as it is or in the form of a pharmaceutical compositionas a mixture with a pharmaceutically acceptable carrier, to a mammal(e.g., human, mouse, rat, rabbit, dog, cat, cattle, horse, pig, monkeyand the like).

[0081] A pharmacologically acceptable carrier employed here may be anyof various organic and inorganic carriers customarily used as apharmaceutical material, such as an excipient, lubricant, binder anddisintegrant for a solid formulation; a solvent, solubilizer, suspendingagent, osmotic agent, buffering agent and pain-suppressing agent for aliquid formulation. A pharmaceutical additives such as a preservative,antioxidant, coloring agent and sweetener can also be used if necessary.

[0082] Preferable examples of the excipient include for example lactose,sugar, D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose,carboxymethylcellulose sodium, gum arabic, dextrin, pullulan, lightanhydrous silicic acid, synthetic aluminum silicate, magnesium aluminatemethasilicate and the like.

[0083] Preferable examples of the lubricant include, for example,magnesium stearate, calcium stearate, talc, colloidal silica and thelike.

[0084] Preferable examples of the binder include, for example, α-starch,sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose,carboxymethylcellulose sodium, crystalline cellulose, sugar, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

[0085] Preferable examples of the disintegrant include, for example,lactose, sugar, starch, carboxymethyl cellulose, carboxymethylcellulosecalcium, croscarmellose sodium, carboxymethyl starch sodium, lightanhydrous silicic acid, low-substituted hydroxypropylcellulose and thelike.

[0086] Preferable examples of the solvent include, for example, waterfor injection, physiological saline, Linger's solution, alcohol,propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil,cottonseed oil and the like.

[0087] Preferable examples of the solubilizing agent include, forexample, polyethylene glycol, propylene glycol, D-mannitol, trehalose,benzyl benzoate, ethanol, tris-aminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate, sodium salicylate,sodium acetate and the like.

[0088] Preferable examples of the suspending agent include, for example,a surfactant such as stearyltriethanolamine, sodium laurylsulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate and the like; a hydrophilic polymer suchas polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulosesodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; a polysolvate and a polyoxyethylenehardened castor oil and the like.

[0089] Preferable examples of the osmotic agent include, for example,sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

[0090] Preferable examples of the buffering agent include, for example,a buffer solution of a phosphate, acetate, carbonate, citrate and thelike.

[0091] Preferable examples of the pain-suppressing agent include, forexample, benzyl alcohol and the like.

[0092] Preferable examples of the preservative include, for example, ap-oxybenzoate, chlorobutanol, benzylalcohol, phenethylalcohol,dehydroacetic acid, sorbic acid and the like.

[0093] Preferable examples of the antioxidant include, for example,sulfite, ascorbate and the like.

[0094] Preferable examples of the colorant include, for example, awater-soluble edible tar dye (e.g., edible dyes such as edible red No.2and No.3, edible yellow No.4 and No.5, edible blue No.1 and No.2), awater-insoluble lake dye (e.g., an aluminum salt of a water-solubleedible tar dye described above), a naturally-occurring dye (e.g.,β-carotine, chlorophyll, colcothar) and the like.

[0095] Preferable examples of the sweetener include, for example,saccharin sodium, dipotassisum glycyrrhetinate, aspartame, steviosideand the like.

[0096] The formulation of the pharmaceutical composition include, forexample, an oral formulation such as tablet, capsule (including softcapsule, microcapsule), granule, powder, syrup, emulsion, suspension andthe like; and a parenteral formulation such as a injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection, intravitreous injection), infusionformulation, external formulation (e.g., nasal formulation, percutaneousformulation, ointment), suppository (e.g., rectal suppository, vaginalsuppository), pellet, dripping formulation and the like, which cansafely be administered through an oral or parenteral route.

[0097] A pharmaceutical composition can be produced by a method usedcustomarily in the field of pharmaceutical preparation, for example, bya method described in Japanese Pharmacopoeia. A typical method forproducing a pharmaceutical preparation is detailed below.

[0098] For example, an oral formulation is produced by adding anexcipient (e.g., lactose, sugar, starch, D-mannitol), disintegrant(e.g., carboxymethylcellulose calcium), binder (e.g., α-starch, gumarabic, carboxymethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone) and lubricant (e.g., talc, magnesium stearate,polyethylene glycol 6000) to an active ingredient, and compressing toshape and then, if necessary, coating with a coating base by a methodknown per se for the purpose of masking of a taste, enteric dissolutionperformance or sustained release.

[0099] Said coating base include, for example, a sugar coating base,water-soluble film coating base, enteric film coating base, sustainedrelease film coating base and the like.

[0100] As a sugar coating base, a sugar is used, and also may be used incombination with one or more kind of base selected from talc,precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnaubawax and the like.

[0101] A water-soluble film coating base include, for example, acellulose-based polymer such as hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,methylhydroxyethylcellulose and the like; a synthetic polymer such aspolyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E[Eudragit E, (trade name), Rohm Pharma], a polyvinylpyrrolidone; apolysaccharide such as pullulan and the like.

[0102] An enteric film coating base include, for example, acellulose-based polymer such as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;an acrylic acid-based polymer such as methacrylic acid copolymer L[Eudragit L (trade name), Rohm Pharma], methacrylic acid copolymer LD[Eudragit L-30D55 (trade name), Rohm Pharma], methacrylic acid copolymerS [Eudragit S (trade name), Rohm Pharma] and the like; and anaturally-occurring material such as shellac.

[0103] A sustained release film coating base include, for example, acellulose-based polymer such as ethylcellulose; and an acrylicacid-based polymer such as an aminoalkylmethacrylate copolymer RS[Eudragit RS (trade name), Rohm Pharma], an ethyl acrylate-methylmethacrylate copolymer suspension [Eudragit NE (trade name), RohmPharma] and the like.

[0104] Two or more of the coating bases described above may be used inadmixture of appropriate proportion. A coating may be supplemented withan opacity-imparting agent such as titanium oxide and Fe₃O₂.

[0105] An injection formulation may be prepared by dissolving,suspending or emulsifying an active ingredient in an aqueous solvent(e.g. distilled water, physiological saline, Linger's solution) or in anoily solvent (e.g., vegetable oil such as olive oil, sesame oil,cottonseed oil and corn oil, propylene glycol) together with adispersant (e.g. polysorbate 80, polyoxyethylene hardened castor oil60), polyethylene glycol, carboxymethylcellulose, sodium alginate,preservative (e.g., methylparaben, propylparaben, benzylalcohol,chlrobutanol, phenol), osmotic agent (e.g., sodium chloride, glycerin,D-mannitol, D-sorbitol, glucose). In this case, if necessary, additivessuch as a solubilizing agent (e.g., sodium salicylate, sodium acetate),stabilizer (e.g., human serum albumin), pain-suppressing agent (e.g.,benzyl alcohol) and the like may be added.

[0106] The daily dose of a hetercyclic compound having an angiotensin IIantagonistic activity or a pharmaceutically acceptable salt thereof usedin this invention is varied depending on the subject to be treated, theadministration route, the disease to be treated and the condition, andfor example in the case of oral administration, about 0.001 to 1000 mg,preferably about 0.1 to 50 mg active ingredient of the heterocycliccompound having an angiotensin II antagonistic activity or apharmaceutically acceptable salt thereof is usually administered to amammal, especially to an adult (50 kg body weight) at a single dose,which is administered preferably once to three times a day.

[0107] A TNF-α inhibitor of this invention can be used as a prophylacticand therapeutic agent for a disease involving the TNF-α to a mammal (forexample, human, mouse, rat, rabbit, dog, cat, cattle, horse, pig,monkey). The disease involving a TNF-α is a disease which is developedor exacerbated as a result of the presence of the TNF-α, and can betreated through an inhibitory effect on the TNF-α. Such a diseaseinclude, for example, an inflammatory disease [e.g., diabeticcomplication such as retinopathy, nephropathy, neuropathy and majorvascular disorders, diabetic nephropathy; arthritis such as chronicrheumatoid arthritis, osteoarthritis, rheumatoid myelitis andperiosteosis; postooperative/posttraumatic inflammation; remedy ofswelling; pharyngitis; cystitis; pneumonia; myocarditis; cardiomyopathy;atopic dermatitis; inflammatory intestinal disease such as Crohn'sdisease and ulcerative colitis; meningitis; inflammatory ophthalmicdisease; inflammatory pulmonary disease such as pneumonia,silicotuberculosis, pulmonary sarcoidosis and pulmonary tuberculosis],circulatory disease (e.g., chronic heart failure including arrhythmia,angina pectris, myocardial infarction, cardiac insufficiency andcongestive heart failure, arteriosclerosis including atherosclerosis,hypertension, deep vein thrombosis, occlusive peripheral circulationfailure, ischemic cerebral circulation failure, disseminatedintravascular coagulation syndrome, Raynaud's disease, Buerger disease),portal hypertension, pulmonary hypertension, allegic disease such asasthma, allergic rhinitis, conjunctivitis, digestive tract allergy,pollinosis and anaphylaxis, chronic occlusive pulmonary disease,collagenosis (e.g., lupus erythematosus, pachyderma, polyarteritis),Crohn's disease, autoimmune hemolytic anemia, psoriasis, hepatic diseasesuch as hepatitis including chronic disease and cirrhosis, pancreaticdisease such as pancreatitis, neurodegenerative disease (e.g.,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,AIDS encephalopathy), central nerve failure (e.g., cerebrovascularfailure such as cerebral hemorrhage and cerebral infarction and itssequela, cranial trauma, spinal damage, cerebral edema, dementia, memoryfailure, consciousness failure, multiple sclerosis), toxemia (e.g.,sepsis, septic shock, endotoxic shock, gram negative sepsis, toxin shocksyndrome), climacteric failure, gestosis, adiposis, hyperlipidemia,hypercholesteremia, abnormal glucose tolerance, solid tumor, tumor(e.g., malignant melanoma, malignant lymphoma, cancer of digestive organ(e.g., stomach, intestine)), cancer and accompanying cachexia, endocrinedisease (Addison disease, Cushing's syndrome, melanocytoma, primaryaldosteronism), Creutzfeldt-Jakob disease, viral infection (e.g.,infections with cytomegalovirus, influenzae virus, herpes virus and thelike), post-percutaneous coronary arterioplasty vascular hypertrophy orocclusion, post-PTCA/stenting/bypass surgery vascularreocclusion/restenosis, post-intervention vascular hypertrophy orocclusion, suppression of implantatin-induced vascular failure andrejection, dialytic hypotension, glaucoma, high ocular tension,myasthenia gravis, chronic defatigation, bone disease (e.g. fracture,re-fracture, osteoporosis, osteomalacia, bone Behet disease, ankylosingspondylitis, chronic rheumatoid arthritis, osteogonarthritis as well asarticular tissue destruction in disease related thereto).

[0108] A TNF-α-inhibitor of the present invention may be used alone in atherapy or may be used in combination with other pharmaceutically activecomponent including hypolipidemic agent or hypocholesteric agent, HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitor,myocardial protecting agent, coronary artery disease-treating agent,other hypertention-treating agent, chronic heart failure-treating agent,diabetes-treating agent, other insulin sensitivity-modifying agent,hypothyroidism-treating agent, nephrosis syndrome-treating agent,anti-inflammatory agent (NSAIDS and the like), bone disease-treatingagent (osteoporosis-treating agent and the like) or chronic renalfailure-treating agent, and in such a case any of these components isadministered preferably as an oral formulation, or as a rectalformulation in the form of a suppository if necessary. A possiblecomponent to be combined as described above include, for example, afibrate [e.g., clofibrate, benzafibrate, GEMFIBRODIL], nicotinic acid,its derivatives and analogues [e.g., ACIPIMOX and probucol], bileacid-binding resin [e.g., cholestyramine, colestipol], cholestrolabsorption inhibitor [e.g., sitosterol, neomycin], squalene epoxidaseinhibitor [e.g., NB-598 and analogues] and the like.

[0109] Other components which can be combined areoxidesqualene-lanosterol cyclase, for example, decalin derivatives,azadecalin derivatives and indan derivatives.

[0110] Hypertension-treating agents: diuretics [e.g., furosemide(Lasix), bumetamide (Lunetoron), azosemide (Diart)], hypotensive agents[e.g., ACE inhibitor (enalapril maleate (Renivace)) and Ca antagonist(manidipine, amlodipine), α or β recepter blockers].

[0111] Chronic heart failure-treating agents: cardiacs [e.g.,cardiotonic glucoside (digoxin and the like), β receptor stimulant(chatecholamine formulation such as denopamine and dobutamine) and PDEinhibitor], diuretics [e.g. furosemide (Lasix), spironolactone(Aldactone)], ACE inhibitors [e.g., enalapril maleate (Renivace)], Caantagonist [e.g., amlodipine] and β receptor blocker.

[0112] Anti-arrhythmic agent: Disopyramide, lidocaine, quinidinesulfate, flecainide acetate, mexiletine hydrochloride, amiodaronehydrochloride and β blocker, Ca antagonist and the like.

[0113] Diabetes-treating agents: Actos, Rosiglidazone, Kinedak, BENFIL,Humulin, Euglucon, Glimicron, Daonil, Nobolin, Monotard, insulins,Glucobay, Dimelin, Rastinon, BASILCON, Deamelin S, Iszilin;

[0114] Hypothyroidism-treating agents: Dried thyroid (Thyreoid), sodiumlevothyroxine (Thyradin S), liothyronidine sodium (Thyronin,Thyronamin);

[0115] Nephrosis syndrome-treating agents: Usually, a first choicesteroid therapy employs prednisolon (Predonine), sodium prednisolonsuccinate (Predonine), sodium methylprednisolon succinate (Solu-medrol),betamethasone (Rinderon) and the like. An anti-coagulation therapyemploys antiplatelets and anti-coagulants such as dipyridamole(BELSANTIN), dilazep hydrochloride (Comelian), tyropidine, clopidogrel,FXa inhibitor;

[0116] HMG-Co A reductase inhibitors: cerivastatin, atrovastatin,pravastatin, simvastatin, itavastatin, lovastatin, fluvastatin,(+)-3R,5S-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-hydroxy-6(E)-heptenoicacid and the like;

[0117] Bone disease-treating agents: calcium formulations (e.g., calciumcarbonate), calcitonin formulations, active vitamin D₃ formulations(e.g., alfacalcidol, (Alfarol and the like), calcitriol (Rocaltrol)),sex hormones (e.g., estrogen, estranediol), hormone formulations [e.g.,conjugated estrogen (Premarin)], IPRIFLAVON formulations (Osten and thelike), vitamin K₂, vitamin K₂ formulations [e.g., menatetrenone (Glakay)and the like], bisphosphonic acid-based formulations (etidronate and thelike), prostaglandin A1, fluorine compounds (e.g., sodium fluoride),osteogenetic protein (BMP), fibroblast growth factor (FGF),platelet-derived growth factor (PDGF), transforming growth factor(TGF-β), insulin-like growth factor-1 and 2 (IGF-1, -2), parathyroidalhormone (PTH), compounds described in EP-A1-376197, EP-A1-460488 andEP-A1-719782 (e.g., (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide)and the like;

[0118] Chronic renal failure-treating agents: diuretics [e.g.,furosemide (Lasix), bumetamide (Lunetoron), azosemide (Diart)],hypotensive agents [e.g., ACE inhibitor (enalapril maleate (Renivace))and Ca antagonist (manidipine), α receptor blocker and the like;

[0119] are combined and administered preferably through an oral route.

[0120] Further, the TNF-α inhibitor of the present invention is usefulfor preventing and treating a thrombosis. In that case, it may be givenalone or in combination with known pharmaceuticals listed below,preferably through an oral route.

[0121] Thrombosis-preventing and treating agents: Anti-coagulants [e.g.,heparin sodium, heparin calcium, warfarin calcium (Warfarin), coagulantfactor Xa inhibitor and coagulation-fibrinogenlytic balance-modifyingagent], thrombolytic agents [e.g., tPA, urokinase], antiplatelet agents[e.g., aspirin, sulfinpyrazone (ANTULAN), dipyridamole (Persantin),ticlopidine (Panaldine), cilostazole (Pletal), GPIIb/IIIa antagonist(ReoPro)] and the like.

[0122] Coronary dilators: Nifedipine, diltiazem, NICORADIL, nitriteformulations and the like.

[0123] Myocardial protectants: heart ATP-K opening agent, Na—H exchangeinhibitor, endothelin antagonist, urotensin antagonist and the like.

[0124] Anti-inflammatory agents: Aspirin, acetaminophen, non-steroidalanti-inflammatory agents [e.g., indomethasin], steroids [e.g.,dexamethasone] and the like.

[0125] Anti-allegic agents: Anti-histamine agents [e.g.,chlorphenylamine maleate], stimulative therapy agents [e.g.,bucillamine], as well as azelastin, seratrodast, tranilast, oxatomide,Stronger Neo-Minophagen C, tranexamic acid, ketotifen fumarate and thelike.

[0126] Anti-tumor agents: Alkylating agents, metabolic antagonists,anti-tumor antibiotic formulations, anti-tumor plant componentformulation and other anti-tumor agents.

[0127] Central nervous system agents: Anti-anxiety agent, hypnoticsedatives, anesthetics, spasmolytic agents, autonomice agents,anti-parkinsonism agents and other psychoneurotic agents.

[0128] Furthermore, anti-obesity agents, anti-rheumatic agents and thelike.

[0129] In addition, a therapy using various biological factors orrespective gene transduction (e.g., ischemic disease therapy usingangiogenesis promoting factors such as HGF and VEGF or respective genetransduciton) and the like.

[0130] A TNF-α inhibitor of the present invention can be used incombination with any of those listed above simultaneously or at acertain time interval.

[0131] When any of those pharmaceuticals is used in combination, eachmay be mixed separately or simultaneously with pharmacologicallyacceptable carrier, excipient, binder, diluent and the like to prepareinto a formulation, which can be administered as a pharmaceuticalcomposition orally or parenterally. When the active ingredients areformulated separately, the resultant individual formulations may bemixed just before use for example using a diluent, while the individualformulations may be given simultaneously or at a certain time intervalto an identical subject. A kit product for administration with mixingindividual formulations just before use using diluent (for example, ainjection kit containing ampoules containing individual powder agentsand a diluent for mixing and dissolving two or more agents just beforeuse) and a kit product for administering separately prepared individualformulations simultaneously or separately at a certain time interval toan identical subject (for example, a kit of tablets for administeringtwo or more tablets simultaneously or separately at a certain timeinterval in which the tablets containing individual agents are placed inan identical or separate bags provided if necessary with the labelindicating the timing of the administration) are also encompassed in apharmaceutical according to the present invention.

[0132] A heterocyclic compound having a angiotensin II antagonisticactivity used in the present invention can be used orally orparenterally, through injection, drip infusion, inhalation, rectaladministration or topical administration, and can be used as it is or asa formulation of a pharmaceutical composition (for example, powder,granule, tablet, pill, capsule, injection, syrup, emulsion, elixir,suspension, solution). That is, a heterocyclic compound having anangiotensin II antagonistic activity according to the present inventioncan be used alone or in a mixture with a pharmaceutically acceptablecarrier (adjuvant, excipient, auxiliary agent and/or diluent).

[0133] A pharmaceutical composition can be formulated by a known method.Such a formulation can be produced usually by mixing/kneading an activeingredient with additives such as an excipient, diluent, carrier and thelike. The term “parenteral” administration employed here means toinclude a subcutaneous injection, intravenous injection, intramuscularinjection, intraperitoneal injection and drip infusion. A formulationfor injection, such as a suspension in an aseptic water for injection oran oily suspension, can be prepared by a method known in the art using asuitable dispersant or wetting agent and suspending agent. The asepticinjection formulation may be an injectable aseptic solution orsuspension in a diluent or solvent which is non-toxic and can be givenparenterally, such as an aqueous solution. Vehicles and solvents whichcan be employed are water, Linger's solution, isotonic saline and thelike. In addition, an aseptic non-volatile oil can usually be employedas a solvent or suspending medium. For this purpose, any non-volatileoil or fatty acid may be employed, including naturally occurring orsynthetic or semi-synthetic fatty oils or fatty acids as well asnaturally occurring or synthetic or semi-synthetic mono-, di- andtriglycerides.

[0134] A suppository for rectal administration can be produced by mixingan active ingredient with a suitable non-irritative auxiliary agentwhich is solid at ambient temperature but liquid at a temperature in anintestine and melts in rectum whereby releasing the active ingredient,such as cocoa butter and polyethylene glycols.

[0135] A solid dosage form for oral administration may for example be apowder, granule, tablet, pill, capsule and the like, as mentioned above.A formulation of such dosage form can be produced by mixing and/orkneading an active ingredient with at least one additive such assucrose, lactose, cellulose sugar, mannitol (D-mannitol), maltitol,dextran, starches (e.g., corn starch), microcrystalline cellulose, agar,alginates, chitins, chitosans, pectins, tragacanth gums, gum arabic,gelatins, collagens, casein, albumin, synthetic or semi-syntheticpolymers or glycerides. Such a dosage form may contain, as usual,further additives such as an inert diluent, lubricant such as magnesiumstearate, preservative such as parabens and sorbic acid, antioxidantsuch as ascorbic acid, α-tocopherol and cysteine, disintegrant (e.g.,sodium croscarmellose), binder (e.g., hydroxypropyl cellulose),thickening agent, buffering agent, sweetener, flavor, perfume and thelike. A tablet or pill may further be enteric-coated. A liquidformulation for oral use includes a pharmaceutically acceptableemulsion, syrup, elixir, suspension and solution, which may contain aninert diluent used ordinarily in the art such as water and may alsocontain additives, if necessary. Such a liquid formulation for oral usecan be produced by a customary method, for example by mixing an activecompound with an inert diluent and other additives if necessary. An oralformulation contain generally 0.01 to 99% by weight, preferably 0.1 to90% by weight, usually 0.5 to 50% by weight of an active compound of thepresent invention, although the amount may vary depending on the dosageforms.

[0136] The dose in a certain patient is decided depending on the age,body weight, general condition, sex, diet, administration time,administration mode, excretion rate, combination of medicaments,severity of the condition being treated, as well as other factors.

[0137] While the daily dose of a TNF-α inhibitor comprising aheterocyclic compound having an angiotensin II antagonistic activityused in this invention or its salt may vary depending on the conditionand the body weight of the patient, type of the compound employed,administration route and the like, it can be administered as aprophylactic/therapeutic agent for an inflammatory disease in adults(about 60 kg body weight) at an oral daily dose of about 0.01 to 1000mg, preferably at about 0.1 to 50 mg as an active ingredient, and at aparenteral daily dose of about 0.001 to 100 mg, preferably at about 0.01to 50 mg, usually about 0.1 to 20 mg as an active ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION

[0138] Hereinafter, the present invention is further detailed by thefollowing Examples, which are not intended to restrict the presentinvention.

EXAMPLES

[0139] A TNF-α inhibitor comprising a heterocyclic compound having anangiotensin II antagonistic activity in this invention or its salt canbe produced for example by the following prescriptions.

Example 1 Capsules

[0140] (1) Candesartan cilexetil 30 mg (2) Lactose 90 mg (3)Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 Capsule200 mg 

[0141] After mixing Components (1), (2), (3) and a half of Component(4), the mixture is granulated. Then the remainder of Component (4) isadded and the entire is filled in gelatin capsules.

Example 2 Tablets

[0142] (1) Candesartan cilexetil 30 mg (2) Lactose 35 mg (3) Corn starch150 mg  (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate  5mg 1 Tablet 250 mg 

[0143] After mixing Components (1), (2), (3), {fraction (2/3)} ofComponent (4) and {fraction (1/2)} of Component (5), the mixture isgranulated. To the resultant granule, the remainder of Components (4)and (5) are added and compressed into tablets.

Experimental Example 1

[0144] TNF-α Inhibiting Effect

[0145] According to the method described in K. Murase et al.,Diabetologia 41: 257-264, 1998, a test drug is administered to modelanimals having obesity and diabetic condition, and by determining thechange in the levels of a TNF-α in blood or tissues, the TNF-αinhibiting effect of the compound of this invention is confirmed.

INDUSTRIAL APPLICABILITY

[0146] A TNF-α inhibitor of the present invention has an excellent TNF-αinhibiting effect and is useful as preventives/remedies for inflammatorydiseases.

1. A TNF-α inhibitor comprising a heterocyclic compound having anangiotensin II antagonistic activity which is represented by theformula:

wherein ring B is an optionally substituted nitrogen-containingheterocyclic ring, R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, and n is an integer of 1 or 2 (except for5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one),or its prodrug or a salt thereof:
 2. An inhibitor according to claim 1,wherein the heterocyclic compound is a compound having an oxygen atom inits molecule.
 3. An inhibitor according to claim 1, wherein theheterocyclic compound is a compound having an ether bond or a carbonylgroup.
 4. An inhibitor according to claim 1, wherein ring B is anoptionally substituted nitrogen-containing aromatic heterocyclic ring.5. An inhibitor according to claim 1, wherein ring B is an optionallysubstituted 5- to 6-membered nitrogen-containing heterocyclic ring. 6.An inhibitor according to claim 1, wherein ring B is an optionallysubstituted imidazole ring.
 7. An inhibitor according to claim 1,wherein the heterocyclic compound is a compound represented by theformula (I):

wherein R¹ is a group capable of forming an anion or a group capable ofbeing converted into such a group, X denotes that a phenylene group anda phenyl group are bound directly or through a spacer having 2 or lessof atomic chains, n is an integer of 1 or 2, ring A is a furtheroptionally substituted benzene ring, R² is a group capable of forming ananion or a group capable of being converted into such a group, R³ is anoptionally substituted hydrocarbon residue which may be bound through aheteroatom.
 8. An inhibitor according to claim 1, wherein theheterocyclic compound is losartan, eprosaltan, candesartan cilexetil,candesartan, telmisartan, irbesartan, olmesartan or tasosartan.
 9. Aninhibitor according to claim 1, wherein the heterocyclic compound is2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid.
 10. An inhibitor according to claim 1, wherein the heterocycliccompound is 1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.11. An inhibitor according to claim 1, wherein the heterocyclic compoundis2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid.
 12. An inhibitor according to claim 1, which is a prophylactic ortherapeutic agent for a disease involving a TNF-α.
 13. An inhibitoraccording to claim 1, which is an antiinflammatory agent.
 14. A methodfor inhibiting a TNF-α in mammals comprising administering to a mammalan effective amount of a heterocyclic compound having an angiotensin IIantagonistic activity which is represented by the formula:

wherein ring B is an optionally substituted nitrogen-containingheterocyclic ring, R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, and n is an integer of 1 or 2 (except for5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one),or its prodrug or a salt thereof.
 15. Use of a heterocyclic compoundhaving an angiotensin II antagonistic activity which is represented bythe formula:

wherein ring B is an optionally substituted nitrogen-containingheterocyclic ring, R¹ is a group capable of forming an anion or a groupcapable of being converted into such a group, X denotes that a phenylenegroup and a phenyl group are bound directly or through a spacer having 2or less of atomic chains, and n is an integer of 1 or 2 (except for5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one),or its prodrug or a salt thereof for producing a TNF-α-inhibitor.